Rule-Based Computational Modeling of Modular Signaling Protein Interactions

Rule-Based Computational Modeling of Modular Signaling Protein Interactions

Dipak Barua¹, James R. Faeder², and Jason M. Haugh³

¹Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI

²Department of Computational Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA

³Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC

Intracellular signal transduction pathways are comprised of complex interactions among cellular proteins and other biomolecules. The structures of signaling proteins/enzymes are often modular, with conserved domains that carry out specific interactions or catalytic functions, and their core activities are dictated through coordinated intra- and inter-molecular interactions. We have applied a computational algorithm for generating large networks of kinetic equations based on a much smaller set of mechanistic rules. Using this rule-based approach, we have formulated kinetic models that account for the modular domain structure of specific signaling proteins, including Shp2 (Src homology-2 domain containing protein tyrosine phosphatase 2), PI3K (phosphoinositide 3-kinase) regulatory subunit, and SH2-B (a Jak2 kinase activating adaptor protein). Analysis of these models reveals the combinatorial possibilities of reactions and interactions that might occur in living cells.